Methods of administering cannabinoids

ABSTRACT

The disclosure provides compositions and methods of treatment by enhanced delivery of cannabinoids using cannabinoid-infused powders comprising a cannabinoid API, an edible carrier, and an edible oil comprising long chain triglycerides.

CROSS-REFERENCE

This application claims the benefit of U.S. Provisional Application Ser.No. 63/309,929, filed Feb. 14, 2022.

FIELD

The present invention relates to methods of treatment comprisingdelivering cannabinoids, e.g., cannabidiol, cannabinol, and/orcannibigerol, via the lymphatic system, thereby providing enhancedbioavailability of the cannabinoid and enhanced delivery of thecannabinoid to the central nervous system, together with formulationsfor use in these methods.

BACKGROUND

Cannabidiol (CBD) is a naturally occurring cannabinoid in the Cannabissativa plant. Cannabinoids are a class of diverse chemical compoundsthat act on cannabinoid receptors in cells that alter neurotransmitterrelease in the brain. There are at least 113 different cannabinoidsisolated from Cannabis, exhibiting varied effects. Cannabidiol is thesecond most prevalent active ingredient of Cannabis extracts and hasbeen studied for many different uses. It is known that cannabidiol lacksthe psychoactive effects seen in many of the other cannabinoidsincluding delta-9-tetrahydrocannabinol (THC). Cannabidiol may havepotential as a treatment for a wide range of medical conditionsincluding arthritis, diabetes, alcohol use disorders, multiplesclerosis, chronic pain, schizophrenia, post-traumatic stress disorder(PTSD), depression, rare white matter disorders, antibiotic-resistantinfections, epilepsy, inflammation, and other neurological disorders.Cannabidiol is a component of pharmaceutical medications currently usedto treat diseases such as multiple sclerosis and epilepsy. For example,an orally administered cannabidiol solution containing sesame oil(Epidiolex®) was approved by the US food and Drug Administration in 2018as a treatment for two rare forms of childhood epilepsy: Lennox-Gastautsyndrome and Dravet syndrome. A nasal spray (Sativex®) containing bothTHC and cannabidiol is used for pain and muscle-tightness in people withmultiple sclerosis.

Cannabidiol is a non-polar compound and has aqueous solubility ofapproximately 0.013 milligrams per milliliter. Furthermore, cannabidiolhas low oral bioavailability and is inconsistently absorbed through thebody's mucous membranes and from the digestive tract into the bloodstream. Clinical studies have reported the oral bioavailability ofcannabidiol as low as approximately 5-10% and absorption has beenreported to fluctuate greatly depending on various factors such as thefat content of meals consumed by the study participants prior to dosingand other factors. Other non-psychoactive cannabinoids found in Cannabisinclude cannabigerol (CBG) and cannabinol (CBN), which have similarlylow solubility and bioavailability.

Cannabidiol has been shown to inhibit SARS-CoV-2 replication, and mayinhibit other viruses as well. Nguyen, et al., “Cannabidiol inhibitsSARS-CoV-2 replication through induction of the host ER stress andinnate immune responses.” Sci. Adv. 8, eabi6110 (2022). Relatively highlevels of cannabidiol are needed to be effective for this use, which aredifficult to obtain given the generally poor bioavailability of thecompound.

Cannabinoid-infused powders comprising a cannabinoid (e.g., CBD, CBG,CBN, or mixtures thereof), an edible carrier, and an edible oilcomprising long chain fatty acids, together with their preparation, aredescribed in U.S. Ser. No. 10/756,180B2, the contents of which areincorporated herein by reference.

There is a need for improved formulations and methods of deliveringcannabinoids, e.g., CBD, to enhance bioavailability and delivery torelevant sites of action.

SUMMARY

It is surprisingly discovered that cannabinoid-infused powderscomprising a cannabinoid (e.g., CBD, CBG, CBN, or combinations thereof),an edible carrier, and an edible oil comprising long chaintriglycerides, e.g., as described in U.S. Ser. No. 10/756,180B2 andrelated applications, are absorbed largely via the lymphatic system,allowing for enhanced bioavailability, enhanced distribution to thecentral nervous system, reduced first-pass effect and metabolism in theliver, reduced food effect, and reduced binding to plasma proteins,relative to formulations that are absorbed into the blood.

In one aspect, the present disclosure provides a method of treating acondition selected from pain, anxiety, nausea, insomnia, and dysphoriaby delivery of a cannabinoid to the lymphatic system, comprising orallyadministering an effective amount of a pharmaceutical compositioncomprising a cannabinoid-infused powder as described herein to a patientin need thereof.

In another aspect, the disclosure provides a method of relieving pain ina patient in need thereof, by delivery of a cannabinoid to the lymphaticsystem, comprising orally administering an effective amount of apharmaceutical composition comprising orally administering acannabinoid-infused powder as described herein, and co-administering anopioid, either separately or as a combined formulation, to a patient inneed thereof, wherein the coadministration of the cannabinoid, e.g.,CBD, lowers the dose of opioid effective to relieve pain.

In another aspect, the disclosure provides methods of enhancing thelymphatic absorption of a cannabinoid API, e.g., CBD or a mixture ofCBD, CBG, and CBN, comprising administering a cannabinoid-infusedpowder, as described herein.

In another aspect, the disclosure provides cannabinoid-infused powderscomprising a cannabinoid, an edible carrier, and an edible oilcomprising long chain triglycerides, wherein the cannabinoid comprises(i) CBD and CBG in a weight ratio of 5-25:1 of CBD:CBG; e.g., about 10:1CBD:CBG or about 25:2 CBD:CBG; (ii) CBD and CBN in a weight ratio of5-25:1 of CBD:CBN; e.g., about 20:1 CBD:CBN or about 27:2 CBD:CBN; or(iii) CBD, CBG and CBN in a weight ratio of 1-10:1-10:1-10(CBD:CBG:CBN).

Further areas of applicability of the present invention will becomeapparent from the detailed description provided hereinafter. It shouldbe understood that the detailed description and specific examples, whileindicating the preferred embodiment of the invention, are intended forpurposes of illustration only and are not intended to limit the scope ofthe invention.

DRAWINGS

FIG. 1 depicts the pharmacokinetics of a powdered formulation of CBDcomprising long chain triglycerides (Formulation D of Example 1) vs. amedium chain triglyceride oil tincture of CBD (MedTerra).

DETAILED DESCRIPTION

Cannabidiol is water insoluble and has low oral bioavailability. Theoral bioavailability of CBD is affected by the first pass effect whichis a phenomenon of drug metabolism whereby the concentration of a drug,specifically when administered orally, is greatly reduced before itreaches the systemic circulation. When CBD is taken orally, it isabsorbed by the digestive system and enters the hepatic portal system.It is carried through the portal vein into the liver before it reachesthe rest of the body. CBD undergoes extensive first pass metabolism andits metabolites are mostly excreted via the bile with a smallerproportion excreted through the kidneys.

The hepatic first-pass metabolism of CBD can be evaded to some extent bylymphatic transport pathway, which is a pathway through which lipids andlipophilic drugs are transported into systemic circulation. In theintestine, lipids are broken into their fatty acid and glycerolcomponents and absorbed into the intestinal enterocyte, where they arereconstructed into triglycerides for packaging into chylomicrons.Chylomicrons are lipoprotein particles that consist of triglycerides,phospholipids, cholesterol, specific proteins and lipid soluble drugs ifthey are present. The chylomicron-associated lipids/drugs are thentransported from the enterocyte into the lymphatic circulation, ratherthan the portal circulation, thus avoiding the first-pass metabolism inthe liver. Shifting CBD absorption from the blood to the lymphaticsystem also facilitates transport of the drug to the brain, reduces foodeffects (i.e., variable absorption due to the contents of the GI tract),and potentially provides a better route of distribution and protectionfrom metabolism than drug bound to albumin and other plasma proteins.

While the foregoing discussion focuses on CBD, other cannabinoids aresubject to similar considerations and so can be advantageouslyadministered in formulations as described herein, e.g., to enhancebioavailability, reduce first-pass metabolism, and improve delivery tothe central nervous system.

It has been found that administration of a cannabinoid-infused powder,comprising cannabinoid (e.g. CBD, CBG, CBN, or combinations thereof), anedible oil comprising long chain triglycerides, and an edible carrier,provides an unexpectedly high delivery of the cannabinoid to thelymphatic system. Without being bound to any theory, it is believed thatthe use of long-chain triglycerides, which require chylomicron formationto enter the body, in contrast to short and medium-chain triglyceridesor no fats, provide lipid soluble drugs such as CBD, CBG, CBN, orcombinations thereof with an alternative, preferable pathway to portalvein absorption.

Many phytocannabinoids act as reuptake inhibitors which allow endogenouscannabinoids to persist longer. While THC binds directly to thecannabinoid receptors, primarily CB1, the minor cannabinoids, includingCBD, seem to be important for reuptake inhibition. A WHO assessmentshows that CBD has low affinity to CB1 and CB2 but promotes activity ofendocannabinoids. Paracetamol is also associated with endocannabinoideffects (FAAH receptors), although the details are not well-understood.There is also interaction between the cannabinoid system and the opiatesystem, so these cannabinoids may potentiate action of opioids, allowingfor lower dose and reduced risk of addition.

The disclosure thus provides a method of relieving pain in a patient inneed thereof, comprising administering an effective amount of apharmaceutical composition comprising a cannabinoid-infused powder asdescribed herein, e.g., any of Compositions 1 et seq. in combinationwith opioid, wherein the coadministration of cannabidiol lowers the doseof opioid required to relieve pain.

In other embodiments, the disclosure provides a method of treating acondition selected from pain, anxiety, nausea, dysphoria, insomnia,neuroinflammation, spasms, epilepsy, inflammation, Alzheimer's Disease,Amyotrophic Lateral Sclerosis (ALS), chronic pain, Diabetes Mellitus,dystonia, epilepsy, fibromyalgia, gastrointestinal disorders,gliomas/cancer, Hepatitis C, Human Immunodeficiency Virus (HIV),Huntington Disease, Hypertension, Incontinence, Methicillin-resistantStaphyloccus aureus (MRSA), Multiple Sclerosis, osteoporosis, pruritus,rheumatoid arthritis, sleep apnea, Parkinson's disease, chronicinflammation, chronic pain, cancer, nausea, vomiting, obesity, epilepsy,glaucoma, asthma, mood disorders, and Tourette Syndrome, comprisingadministering an effective amount of a pharmaceutical compositioncomprising a cannabinoid-infused powder as described herein, e.g., anyof Compositions 1 et seq. to a patient in need thereof.

For example, the disclosure provides a method of treating a conditionselected from pain, anxiety, nausea, insomnia, and dysphoria comprisingadministering an effective amount of a pharmaceutical compositioncomprising a cannabinoid-infused powder as described herein, e.g., anyof Compositions 1 et seq. to a patient in need thereof.

The pharmaceutical composition comprising a cannabinoid-infused powderas described herein, e.g., any of Compositions 1 et seq., as describedherein comprises an edible oil comprising long chain triglycerides. Longchain triglycerides are triglycerides of long chain fatty acids, e.g.,fatty acids having from C₁₃ to C₂₄ carbon atoms, for exampletriglycerides of C₁₆ fatty acids, C₁₈ fatty acids, and mixtures thereof.The fatty acid may be saturated or unsaturated. For example, the edibleoil comprising long chain triglycerides may be selected from vegetable,nut, or seed oils (such as coconut oil, peanut oil, soybean oil,safflower seed oil, corn oil, olive oil, castor oil, cottonseed oil,arachis oil, sunflower seed oil, coconut oil, palm oil, rapeseed oil,evening primrose oil, grape seed oil, wheat germ oil, sesame oil,avocado oil, almond oil, borage oil, peppermint oil, apricot kernel oil,and/or hemp oil) and animal oils (such as fish liver oil, shark oiland/or mink oil), and mixtures thereof. In some embodiments, thecannabinoid infused powder may further comprise medium chaintriglycerides, mono- or di-glycerides, and poly-ethoxylated derivativesof glycerides, e.g., the cannabinoid infused powder may comprisecomponents selected from sesame oil, anise oil, apricot kernel oil,apricot kernel oil PEG-6 esters, borage oil, canola oil, castor oil,castor oil polyoxyl 35, castor oil polyoxyl 40, castor oil polyoxyl 40hydrogenated, castor oil polyoxyl 60, castor oil polyoxyl 60hydrogenated castor oil hydrogenated, cinnamon oil, clove oil, coconutoil, coconut oil-lecithin, coconut oil fractioned, coriander oil, cornoil, corn oil PEG-6 esters (Labrafil® M 2125 CS; PEG-6-glyceryllinoleate), corn oil PEG-8 esters, cottonseed oil, cottonseed oilhydrogenated, kernel oil, kernel oil PEG-6 esters, lemon oil, mineraloil, mineral oil (light), neutral oil, nutmeg oil, olive oil, olive oilPEG-6 esters, orange oil, palm kernel oil, palm kernel oil/hydrogenated,palm kernel oil PEG-6 esters, peanut oil, peanut oil PEG-6 esters,peppermint oil, poppy seed oil, safflower oil, sunflower oil, soybeanoil, soybean oil hydrogenated, soybean oil refined, triisostearin PEG-6esters, vegetable oil, vegetable oil hydrogenated, vegetable oilsglyceride hydrogenated, vegetable oil PEG esters, triolein, trilinolein,trilinolenin, glycerol esters of saturated C8-C18 fatty acids (Gelucire®33/01), glyceryl esters of saturated C12-C18 fatty acids (Gelucire®39/01 and 43/01), glyceryl behenate, glyceryl distearate, glycerylisostearate, glyceryl laurate, glyceryl laurate/PEG-32 laurate(Gelucire® 44/14), glyceryl monooleate (Peceol®), glyceryl monolinoleate(Maisine® CC; also known as corn oil mono-, di-, and triglycerides),glyceryl mono and dicaprylocaprate (Masester E8120), glyceryl palmitate,glyceryl palmitostearate, glyceryl palmitostearate/PEG-32 (Gelucire®50/13) palmitostearate glyceryl ricinoleate, glyceryl stearate, glycerylstearate/PEG stearate, glyceryl stearate/PEG-32 stearate (Gelucire®53/10), glyceryl stearate/PEG-40 stearate, glyceryl stearate/PEG-75stearate, glyceryl stearate/PEG-100 stearate, polyglyceryl 10-oleate,polyglyceryl 3-oleate, polyglyceryl 4-oleate, polyglyceryl10-tetralinoleate, polyoxyl 100 glyceryl stearate, and saturatedpolyglycolized glycerides (Gelucire® 37/02 and Gelucire® 50/02),caprylic/capric glycerides, caprylic/capric glycerides derived fromcoconut oil or palm seed oil (e.g. Labrafac®, Miglyol® 810, 812,Crodamol GTCC-PN, Softison® 378), propylene glycol caprylate/caprate(Labrafac® PC), propylene glycol dicaprylate/dicaprate (Miglyol® 840),medium chain (C8/C10) mono- and diglycerides (Capmul® MCM, Capmul® MCM(L)), and glycerol esters of saturated C8-C18 fatty acids (Gelucire®33/01), and mixtures thereof.

In particular embodiments, the edible oil comprising long chaintriglycerides is substantially free of short- or medium-chaintriglycerides, e.g., wherein the fatty acid content of the edible oilcomprising long chain triglycerides consists of at least 95%, e.g., atleast 98%, C16 and/or C18 fatty acids.

The pharmaceutical compositions of the present invention comprisingcannabinoid infused powder may further comprise one or more surfactants,either as part of the cannabinoid infused powder, or in addition to thecannabinoid infused powder, e.g., in an amount of 15-70% by weight ofthe composition, e.g., in an amount of 20-65% by weight of thecomposition. Surfactants have a property referred to ashydrophilic-lipophilic balance (HLB), which is a measure of howhydrophilic or lipophilic a given surfactant, or surfactant blend is.The HLB of surfactants generally ranges from 0 to 20, with 0 being themost lipophilic and 20 being the most hydrophilic. Surfactants used toproduce oil-in-water emulsions often fall within the range of about 8 to16 on the HLB scale. In some embodiments, the total surfactants in thecomposition have an overall HLB of about 12 or higher, which assists information of small droplets. Non-ionic surfactants are preferred, asthese are generally less toxic than ionic surfactants. For example, thesurfactants may be selected from polysorbate 20 (Tween® 20), polysorbate80 (Tween® 80), polyethyleneglycol 660 12-hydroxystearate (Solutol®HS-15), TPGS (d-α-tocopheryl polyethylene glycol 1000 succinate),sorbitan monolaurate, sorbitan monopalmitate, sorbitan monoleate (Span®20), sorbitan monostearate and sorbitan tristearate,polyoxyethylene-polyoxypropylene block copolymers, e.g., Poloxamer 338,Poloxamer 407, Poloxamer, 237, Poloxamer, 217, Poloxamer 124, Poloxamer184, Poloxamer 185, almond oil PEG-6 esters, almond oil PEG-60 esters,apricot kernel oil PEG-6 esters (Labrafil® M1944CS), caprylic/caprictriglycerides PEG-4 esters (Labrafac® Hydro WL 1219), caprylic/caprictriglycerides PEG-4 complex (Labrafac® Hydrophile), caprylic/capricglycerides PEG-6 esters (Softigen® 767), caprylic/capric glyceridesPEG-8 esters (Labrasol®), castor oil PEG-50 esters, hydrogenated castoroil PEG-5 esters, hydrogenated castor oil PEG-7 esters, 9 hydrogenatedcastor oil PEG-9 esters, corn oil PEG-6 esters (Labrafil® M 2125 CS;PEG-6-glyceryl linoleate), corn oil PEG-8 esters (Labrafil® WL 2609 BS),corn glycerides PEG-60 esters, olive oil PEG-6 esters (Labrafil® M1980CS), hydrogenated palm/palm kernel oil PEG-6 esters (Labrafil® M 2130BS), hydrogenated palm/palm kernel oil PEG-6 esters with palm kerneloil, PEG-6, palm oil (Labrafil® M 2130 CS), palm kernel oil PEG-40esters, peanut oil PEG-6 esters (Labrafil® M 1969 CS), glycerol estersof saturated C8-C18 fatty acids (Gelucire® 33/01), glyceryl esters ofsaturated C12-C18 fatty acids (Gelucire® 39/01 and 43/01), glyceryllaurate/PEG-32 laurate (Gelucire® 44/14), glyceryl laurate glyceryl/PEG20 laurate, glyceryl laurate glyceryl/PEG 32 laurate, glyceryl, laurateglyceryl/PEG 40 laurate, glyceryl oleate/PEG-20 glyceryl, glyceryloleate/PEG-30 oleate, glyceryl palmitostearate/PEG-32 palmitostearate(Gelucire® 50/13), glyceryl stearate/PEG stearate, glycerylstearate/PEG-32 stearate (Gelucire® 53/10), saturated polyglycolizedglycerides (Gelucire® 37/02 and Gelucire® 50/02), triisostearin PEG-6esters (i.e. Labrafil® Isostearique), triolein PEG-6 esters, trioleatePEG-25 esters, polyoxyl 35 castor oil (Cremophor® EL), polyoxyl 40hydrogenated castor oil (Cremophor® RH 40), polyoxyl 60 hydrogenatedcastor oil (Cremophor® RH60), PEG-8 caproate, PEG-8 caprylate, PEG-8caprate PEG-8 laurate, PEG-8 oleate, PEG-8 stearate, PEG-9 caproate,PEG-9 caprylate, PEG-9 caprate PEG-9 laurate, PEG-9 oleate, PEG-9stearate, PEG-10 caproate, PEG-10 caprylate, PEG-10 caprate PEG-10laurate, PEG-10 oleate, PEG-10 stearate, PEG-10 laurate, PEG-12 oleate,PEG-15 oleate, PEG-20 laurate, PEG-20 oleate, caprylate/capratediglycerides, glyceryl monooleate, glyceryl ricinoleate, glyceryllaurate, glyceryl dilaurate, glyceryl dioleate, glyceryl mono/dioleate,glyceryl caprylate/caprate, medium chain (C8/C10) mono- and diglycerides(Capmul® MCM, Capmul® MCM (L)), mono- and diacetylated monoglycerides,polyglyceryl oleate, polyglyceryl-2 dioleate, polyglyceryl-10 trioleate,polyglyceryl-10 laurate, polyglyceryl-10 oleate, and polyglyceryl-10mono dioleate, propylene glycol caprylate/caprate (Labrafac® PC),propylene glycol dicaprylate/dicaprate (Miglyol® 840), propylene glycolmonolaurate, propylene glycol ricinoleate, propylene glycol monooleate,propylene glycol dicaprylate/dicaprate, propylene glycol dioctanoate,PEG-20 sorbitan monolaurate, PEG-20 sorbitan monopalmitate, PEG-20sorbitan monostearate, and PEG-20 sorbitan monooleate, and mixturesthereof. In some embodiments, the one or more surfactants may comprisepolysorbate 80, or polysorbate 80 and polyoxyl 35 castor oil (Cremophor®EL).

In some embodiments, the pharmaceutical composition is substantiallysurfactant-free, e.g., wherein the pharmaceutical composition containsless than 1% of surfactants (other than impurities derived from theedible oil comprising long chain triglycerides, such as long chain fattyacids or mono or di-glycerides of long chain fatty acids).

In some embodiments, the inclusion of one or more non-polar antioxidantsin the pharmaceutical composition, either as part of the cannabinoidinfused powder, or in addition to the cannabinoid infused powder, may bebeneficial to slow or halt the degradation of the non-polar activeingredient(s). These oil-soluble antioxidants are ideally selected frommixed tocopherols, quercetin, curcumin or other suitable oil-solubleantioxidants, with the ability to slow or halt the degradation of thenon-polar active ingredient(s).

In some embodiments, the addition of anti-bacterial and/or anti-fungalagents to the pharmaceutical composition, either as part of thecannabinoid infused powder, or in addition to the cannabinoid infusedpowder, may be beneficial. These anti-bacterial and/or anti-fungalagents may be, for example, non-polar, natural anti-bacterial and/oranti-fungal agents selected from among thymol, carvacrol, lauric acid,or other naturally occurring anti-bacterial and/or anti-fungal agents.

The disclosure thus provides a method (Method 1) of

-   -   a. treating a condition responsive to cannabinoid therapy, e.g.        selected from pain, anxiety, nausea, insomnia, and dysphoria, by        delivery of a cannabinoid to the lymphatic system, or    -   b. enhancing delivery of a cannabinoid, e.g., CBD, CBG, and/or        CBN, to the lymphatic system; or    -   c. enhancing delivery of a cannabinoid, e.g., CBD, CBG, and/or        CBN, to the central nervous system; or    -   d. reducing first pass metabolism of a cannabinoid, e.g., CBD,        CBG, and/or CBN; or    -   e. reducing food effects in administration of a cannabinoid,        e.g., CBD, CBG, and/or CBN;    -   f. reducing the dose of opiate needed to relieve pain in a        patient receiving opioid treatment; or    -   g. treating, mitigating, or inhibiting a condition responsive to        CBD, e.g., a viral infection, e.g. a SARS-CoV-2 infection;    -   comprising orally administering to a patient in need thereof, an        effective amount of a pharmaceutical composition comprising a        cannabinoid-infused powder, wherein the cannabinoid-infused        powder comprises a cannabinoid active pharmaceutical ingredient        (API)(e.g. CBD, CBG, CBN, or combinations thereof), an edible        oil comprising long chain triglycerides, and an edible carrier.

For example, in particular embodiments the disclosure provides:

-   -   1.1. Method 1, wherein the active pharmaceutical ingredient        (API) is free or substantially free of        delta-9-tetrahydrocannabinol (THC).    -   1.2. Method 1 or 1.1 wherein the API contains less than 0.03%,        less than 0.01%, less than 0.001%, less than 0.0001%, or less        than 0.00001% THC by weight of delta-9-tetrahydrocannabinol        (THC).    -   1.3. Any foregoing Method, wherein the API is a CBD-rich hemp        extract.    -   1.4. Any foregoing Method, wherein the API is a CBD-rich cold        distillate of Cannabis plant material, e.g., comprising greater        than 90% of cannabinoids and less than 10% of other materials        from the plant.    -   1.5. Any foregoing Method, wherein the API comprises CBD.    -   1.6. Any foregoing Method wherein the API comprises CBG.    -   1.7. Any foregoing Method wherein the API comprises CBN.    -   1.8. Any foregoing Method, wherein the API comprises CBD and        CBG.    -   1.9. Any foregoing Method, wherein the API comprises CBD and        CBN.    -   1.10. Any foregoing Method, wherein the API comprises CBD, CBG        and CBN.    -   1.11. Any foregoing Method wherein the API comprises CBD and CBG        in a weight ratio of 5-25:1 of CBD:CBG; e.g., about 10:1 CBD:CBG        or about 25:2 CBD:CBG.    -   1.12. Any foregoing Method wherein the API comprises CBD and CBG        in a weight ratio of 5-25:1 of CBD:CBN; e.g., about 20:1 CBD:CBN        or about 27:2 CBD:CBN.    -   1.13. Any foregoing Method wherein the API comprises CBD, CBG        and CBN in a weight ratio of 5-25:1-5:1-5 (CBD:CBG:CBN).    -   1.14. Any foregoing Method, wherein the cannabinoid present in        the API comprises a synthetic cannabidiol.    -   1.15. Any foregoing Method, wherein the API consists of        cannabinoids selected from CBD, CBG, CBN, and mixtures thereof,        e.g., wherein the API is substantially free of THC, e.g.,        wherein the API is substantially free of cannabinoids other than        CBD, CBG, CBN, and mixtures thereof, e.g., wherein the API        contains less than 0.1% of THC, e.g., wherein the API contains        less than 0.1% of cannabinoids other than CBD, CBG, CBN, and        mixtures thereof.    -   1.16. Any foregoing Method, wherein the API consists of CBD,        CBG, and CBN, e.g., is substantially free of other cannabinoids,        e.g., contains less than 0.1% of other cannabinoids.    -   1.17. Any foregoing Method, wherein the API is present in an        amount of 2-15%, 5-15%, 2-10%, 5-10%, 10-15%, 8-12%, about 6%,        about 7%, or about 8% by weight of the pharmaceutical        composition.    -   1.18. Any foregoing Method wherein the API is supplied in a hemp        distillate comprising CBD and CBG and/or CBN and substantially        free of THC, e.g. less than 0.1% THC.    -   1.19. Any foregoing Method wherein the pharmaceutical        composition is in unit dose form, e.g., capsule form.    -   1.20. Any foregoing Method wherein the pharmaceutical        composition is in capsule form, wherein each capsule comprises        20-30 mg CBD and 1-3 mg CBG and/or CBN.    -   1.21. Any foregoing Method, wherein the edible oil comprising        long chain triglycerides is selected from vegetable, nut, or        seed oils (such as coconut oil, peanut oil, soybean oil,        safflower seed oil, corn oil, olive oil, castor oil, cottonseed        oil, arachis oil, sunflower seed oil, coconut oil, palm oil,        rapeseed oil, evening primrose oil, grape seed oil, wheat germ        oil, sesame oil, avocado oil, almond oil, borage oil, peppermint        oil, apricot kernel oil, and/or hemp oil) and animal oils (such        as fish liver oil, shark oil and/or mink oil), and mixtures        thereof.    -   1.22. Any foregoing Method, wherein the edible oil comprising        long chain triglycerides comprises sunflower seed oil.    -   1.23. Any foregoing Method, wherein the edible oil comprising        long chain triglycerides comprises hemp oil.    -   1.24. Any foregoing Method, wherein the edible oil comprising        long chain triglycerides comprises a mixture of sunflower seed        oil and hemp oil.    -   1.25. Any foregoing Method, wherein the edible oil comprising        long chain triglycerides is substantially free of short- or        medium-chain triglycerides, e.g., wherein the fatty acid content        of the edible oil comprising long chain triglycerides consists        of at least 95%, e.g., at least 98%, C₁₆ and/or C₁₈ fatty acids.    -   1.26. Any foregoing method wherein the fatty acids in the edible        oil comprising ling chain triglycerides comprise a mixture of        palmitic acid, stearic acid, oleic acid, and linoleic acid.    -   1.27. Any foregoing method wherein the fatty acids in the edible        oil comprising ling chain triglycerides comprise at least 60%,        e.g., at least 80%, of a mixture of oleic acid and linoleic        acid.    -   1.28. Any foregoing Method, wherein the edible carrier comprises        one or more substances selected from dried plant material (e.g.,        tea leaves, coffee beans, cocoa powder, gingko balboa powder,        and/or ginseng powder), milk powder, starch (e.g., tapioca        starch), silicon dioxide, and mixtures thereof.    -   1.29. Any foregoing Method, wherein the edible carrier comprises        tapioca starch and silicon dioxide.    -   1.30. Any foregoing Method, wherein the edible carrier comprises        tapioca starch, silicon dioxide, gingko balboa powder, and        ginseng powder.    -   1.31. Any foregoing Method wherein the pharmaceutical        composition further comprises melatonin.    -   1.32. Any foregoing method wherein    -   the API comprises (a) 4%-6% CBD and (b) 0.2% to 0.7% CBG and/or        0.2% to 0.7% CBN, by weight of the cannabinoid-infused powder;    -   the edible oil comprises 5-10% sunflower seed oil, by weight of        the cannabinoid-infused powder; and    -   the edible carrier is selected from silicon dioxide, starch, e.g        tapioca starch, dried plant material (e.g., ginseng powder and        gingko balboa powder), and mixtures thereof, and comprises        80%-90% by weight of the cannabinoid infused powder.    -   1.33. Any foregoing Method wherein the cannabinoid-infused        powder is obtained or obtainable by contacting the edible        carrier with an edible oil comprising the cannabinoid active        pharmaceutical ingredient and a second edible oil, and drying        and pulverizing the infused edible carrier thus obtained.    -   1.34. Any foregoing Method wherein, after oral administration,        at least 40%, e.g., at least 50%, e.g., at least 60%, of the API        absorbed is absorbed via the lymphatic system rather than the        portal vein absorption, e.g., as measured in rats with        cannulated intestinal lymph duct and portal veins, e.g., as        described in Example 2.    -   1.35. Any foregoing Method wherein the liver metabolism of the        API within one hour of oral administration is reduced relative        to the liver metabolism of the API within one hour of oral        administration of a formulation that does not comprise long        chain triglycerides.    -   1.36. Any foregoing Method wherein, after oral administration,        the total bioavailability of the API is at least 70%, e.g., at        least 80%, e.g., at least 90%.    -   1.37. Any foregoing Method wherein the bioavailability after        oral administration is substantially the same, e.g., ±10%, in        fed and fasted subjects.    -   1.38. Any foregoing Method wherein, after oral administration,        the API is present in the cerebrospinal fluid (CSF) at levels        greater than the levels in the plasma.    -   1.39. Any foregoing Method wherein the cannabinoid-infused        powder is provided in a unit dose form, e.g., in a capsule or        tablet.    -   1.40. Any foregoing Method wherein the cannabinoid-infused        powder is provided in a unit dose form, e.g., in a capsule or        tablet, comprising API in the amount of 20-100 mg.    -   1.41. Any foregoing Method wherein the cannabinoid-infused        powder is provided in a unit dose form, e.g., in a capsule or        tablet, wherein the API comprises 10-50 mg CBD.    -   1.42. Any foregoing Method wherein the cannabinoid-infused        powder is provided in a unit dose form, e.g., in a capsule or        tablet, wherein the API comprises 10-50 mg CBD and 1-5 mg CBG.    -   1.43. Any foregoing Method wherein the cannabinoid-infused        powder is provided in a unit dose form, e.g., in a capsule or        tablet, wherein the API comprises 10-50 mg CBD and 1-5 mg CBN.    -   1.44. Any foregoing Method wherein the cannabinoid-infused        powder is provided in a unit dose form, e.g., in a capsule or        tablet, wherein the API comprises 10-50 mg CBD, 1-5 mg CBG, and        1-5 mg CBN.    -   1.45. Any foregoing Method wherein the API is administered in a        daily dose of 20-100 mg of cannabinoid, e.g., wherein the API is        administered in a daily dose comprising 10-50 mg CBD; or 10-50        mg CBD and 1-5 mg CBG; or 10-50 mg CBD and 1-5 mg CBN; or 10-50        mg CBD, 1-5 mg CBG, and 1-5 mg CBN.    -   1.46. Any foregoing Method which is a method of treating a        condition responsive to cannabinoid therapy, by delivery of a        cannabinoid to the lymphatic system, wherein the condition is        selected from pain, anxiety, nausea, dysphoria, insomnia,        neuroinflammation, spasms, epilepsy, inflammation, Alzheimer's        Disease, Amyotrophic Lateral Sclerosis (ALS), chronic pain,        Diabetes Mellitus, dystonia, epilepsy, fibromyalgia,        gastrointestinal disorders, gliomas/cancer, Hepatitis C, Human        Immunodeficiency Virus (HIV), Huntington Disease, Hypertension,        Incontinence, Methicillin-resistant Staphyloccus aureus (MRSA),        Multiple Sclerosis, osteoporosis, pruritus, rheumatoid        arthritis, sleep apnea, Parkinson's disease, chronic        inflammation, chronic pain, cancer, nausea, vomiting, obesity,        epilepsy, glaucoma, asthma, mood disorders, and Tourette        Syndrome.    -   1.47. Any foregoing Method which is a method of treating a        condition selected from pain, anxiety, nausea, insomnia, and        dysphoria by delivery of a cannabinoid to the lymphatic system.    -   1.48. Any foregoing Method which is a method of enhancing        delivery of a cannabinoid, e.g., CBD, CBG, and/or CBN, to the        lymphatic system.    -   1.49. Any foregoing Method which is a method of enhancing        delivery of a cannabinoid, e.g., CBD, CBG, and/or CBN, to the        central nervous system.    -   1.50. Any foregoing Method which is a method of reducing first        pass metabolism of a cannabinoid, e.g., CBD, CBG, and/or CBN.    -   1.51. Any foregoing Method which is a method of reducing food        effects in administration of a cannabinoid, e.g., CBD, CBG,        and/or CBN.    -   1.52. Any foregoing Method which is a method of reducing the        dose of opiate needed to relieve pain in a patient receiving        opioid treatment.    -   1.53. Any foregoing Method which is a method of relieving pain        in a patient in need thereof, by delivery of a cannabinoid to        the lymphatic system, comprising orally administering an        effective amount of a pharmaceutical composition comprising a        cannabinoid-infused powder in accordance with any foregoing        Method, and further comprising co-administering an opioid,        either separately or as a combined formulation, to the patient        in need thereof, wherein the coadministration of the        cannabinoid-infused powder lowers the dose of opioid effective        to relieve pain.    -   1.54. Any foregoing Method which is a method of treating,        inhibiting or mitigating a SARS-CoV-2 infection, e.g. by        delivering an amount of CBD effective to inhibit SARS-CoV-2        replication through induction of host ER stress and innate        immune responses.    -   1.55. Any foregoing Method wherein the pharmaceutical        composition is a composition according to any of Compositions 1,        et seq. below.

The cannabinoid-infused powders for use in the methods of the disclosuremay contain an active pharmaceutical ingredient (API) containingcannabidiol (CBD), e.g., a mixture of CBD, CBG and CBN. In certainembodiments, the active pharmaceutical ingredient (API) is free orsubstantially free of delta-9-tetrahydrocannabinol (THC), e.g. containsless than 0.03%, less than 0.01%, less than 0.001%, less than 0.0001%,or less than 0.00001% THC by weight of the API. In some embodiments, theAPI is a CBD-rich hemp extract. As used herein, the term “hemp” refersto cannabis that contains 0.3% or less THC by dry weight. The CBD-richhemp extract may be prepared by any method known in the art. Forexample, cannabinoids may be extracted from dried hemp leaves of thethree species Cannabis sativa, Cannabis indica, and Cannabis ruderalisusing a hydrocarbon solvent such as butane, a supercritical solvent suchas carbon dioxide, or ethanol. The hemp extracts may be processed toremove THC and enrich CBD by purification steps such as columnchromatography. The API may comprise other cannabidiols such ascannabigerol (CBG) and/or cannabinol (CBN). In some embodiments, the APIcomprises CBD, CBG and CBN, optionally wherein the CBD, CBG and CBN arepresent in a weight ratio of 1-10:1-10:1-10 (CBD:CBG:CBN). In otherembodiments, the cannabidiol present in the API may be a syntheticcannabidiol. As used herein, the term “synthetic cannabidiol” refers tocannabidiol that is manufactured using chemical means rather thanobtained from hemp plant. Cannabidiol may be manufactured by any methodknown in the art. In some embodiments, the API does not contain anycannabinoid other than CBD. In other embodiments, the API comprisesother cannabidiols such as cannabigerol (CBG) and cannabinol (CBN). Insome embodiments, the API comprises CBD, CBG and CBN, optionally whereinthe CBD, CBG and CBN are present in a weight ratio of 1-10:1-10:1-10(CBD:CBG:CBN).

For example, the API may be present in an amount of 1-15% by weight ofthe composition. In some embodiments, the API is present in an amount of2-15%, 5-15%, 2-10%, 5-10%, 10-15%, 8-12%, or about 10% by weight of thecomposition.

For example, the disclosure further provides a pharmaceuticalcomposition (Composition 1) comprising a cannabinoid-infused powdercomprising a cannabinoid active pharmaceutical ingredient (API)(e.g.CBD, CBG, CBN, or combinations thereof), an edible carrier, and anedible oil comprising long chain triglycerides.

-   -   1.1. Composition 1, wherein the cannabinoid-infused powder is        provided in a unit dose form, e.g., in a capsule or tablet,        wherein the API comprises 10-50 mg CBD.    -   1.2. Any foregoing Composition wherein, wherein the cannabinoid        API comprises    -   (i) CBD and CBG in a weight ratio of 5-20:1 of CBD:CBG; e.g.,        about 10:1 CBD:CBG or about 25:2 CBD:CBG;    -   (ii) CBD and CBN in a weight ratio of 5-20:1 of CBD:CBN; e.g.,        about 10:1 CBD:CBN or about 27:2 CBD:CBN; or    -   (iii) CBD, CBG and CBN in a weight ratio of 1-10:1-10:1-10        (CBD:CBG:CBN); e.g.,    -   1.3. Any foregoing Composition wherein the cannabinoid-infused        powder is provided in a unit dose form, e.g., in a capsule or        tablet, wherein the API comprises 10-50 mg CBD and 1-5 mg CBG.    -   1.4.Any foregoing Composition wherein the cannabinoid-infused        powder is provided in a unit dose form, e.g., in a capsule or        tablet, wherein the API comprises 10-50 mg CBD and 1-5 mg CBN.    -   1.5.Any foregoing Composition wherein the cannabinoid-infused        powder is provided in a unit dose form, e.g., in a capsule or        tablet, wherein the API comprises 10-50 mg CBD, 1-5 mg CBG, and        1-5 mg CBN.    -   1.6.Any foregoing Composition, wherein the cannabinoid present        in the API comprises a synthetic cannabidiol.    -   1.7.Any foregoing Composition, wherein the API consists of        cannabinoids selected from CBD, CBG, CBN, and mixtures thereof,        e.g., wherein the API is substantially free of THC, e.g.,        wherein the API is substantially free of cannabinoids other than        CBD, CBG, CBN, and mixtures thereof, e.g., wherein the API        contains less than 0.1% of THC, e.g., wherein the API contains        less than 0.1% of cannabinoids other than CBD, CBG, CBN, and        mixtures thereof.    -   1.8.Any foregoing Composition, wherein the API consists of CBD,        CBG, and CBN, e.g., is substantially free of other cannabinoids,        e.g., contains less than 0.1% of other cannabinoids.    -   1.9. Any foregoing Composition, wherein the API is present in an        amount of 2-15%, 5-15%, 2-10%, 5-10%, 10-15%, 8-12%, or about        10% by weight of the pharmaceutical composition.    -   1.10. Any foregoing Composition, wherein the edible oil        comprising long chain triglycerides is selected from vegetable,        nut, or seed oils (such as coconut oil, peanut oil, soybean oil,        safflower seed oil, corn oil, olive oil, castor oil, cottonseed        oil, arachis oil, sunflower seed oil, coconut oil, palm oil,        rapeseed oil, evening primrose oil, grape seed oil, wheat germ        oil, sesame oil, avocado oil, almond oil, borage oil, peppermint        oil, apricot kernel oil, and/or hemp oil) and animal oils (such        as fish liver oil, shark oil and/or mink oil), and mixtures        thereof.    -   1.56. Any foregoing Composition, wherein the edible oil        comprising long chain triglycerides comprises sunflower seed        oil.    -   1.57. Any foregoing Composition, wherein the edible oil        comprising long chain triglycerides comprises hemp oil.    -   1.58. Any foregoing Composition, wherein the edible oil        comprising long chain triglycerides comprises a mixture of        sunflower seed oil and hemp oil.    -   1.59. Any foregoing Method, wherein the edible oil comprising        long chain triglycerides is substantially free of short- or        medium-chain triglycerides, e.g. wherein 95%, e.g. 98%, of the        triglyceride content of the pharmaceutical composition consists        of triglycerides comprising C₁₆ and/or C₁₈ fatty acids.    -   1.60. Any foregoing Composition wherein the fatty acids in the        edible oil comprising ling chain triglycerides comprise a        mixture of palmitic acid, stearic acid, oleic acid, and linoleic        acid.    -   1.61. Any foregoing Composition wherein the fatty acids in the        edible oil comprising ling chain triglycerides comprise at least        60%, e.g., at least 80%, of a mixture of oleic acid and linoleic        acid.    -   1.62. Any foregoing Composition, wherein the edible carrier        comprises one or more substances selected from dried plant        material (e.g., tea leaves, coffee beans, cocoa powder, gingko        balboa powder, and/or ginseng powder), milk powder, starch        (e.g., tapioca starch), silicon dioxide, and mixtures thereof.    -   1.63. Any foregoing Composition, wherein the edible carrier        comprises tapioca starch and silicon dioxide.    -   1.64. Any foregoing Composition, wherein the edible carrier        comprises tapioca starch, silicon dioxide, gingko balboa powder,        and ginseng powder.    -   1.65. Any foregoing Composition wherein the pharmaceutical        composition further comprises melatonin.    -   1.66. Any foregoing Composition wherein        -   the API comprises 4%-6% CBD and 0.2% to 0.7% CBG or 0.2% to            0.7% CBN, by weight of the cannabinoid-infused powder;        -   the edible oil comprises 5-10% sunflower seed oil, by weight            of the cannabinoid-infused powder; and        -   the edible carrier is selected from silicon dioxide, starch,            e.g tapioca starch, dried plant material (e.g., ginseng            powder and gingko balboa powder), and mixtures thereof, and            comprises 80%-90% by weight of the cannabinoid infused            powder.    -   1.67. Any foregoing Composition wherein the cannabinoid-infused        powder is obtained or obtainable by contacting the edible        carrier with an edible oil comprising the cannabinoid active        pharmaceutical ingredient and a second edible oil, and drying        and pulverizing the infused substance thus obtained.    -   1.68. Any previous Composition, further comprising one or more        surfactants, e.g., in an amount of 20-65% by weight of the        composition.    -   1.69. Any previous Composition, further comprising one or more        surfactants, wherein the one or more surfactants have a HLB of        about 8 to 16.    -   1.70. Any previous Composition, further comprising one or more        surfactants, wherein the total surfactants in the composition        have an overall HLB of about 12 or higher.    -   1.71. Any previous Composition, further comprising one or more        surfactants, wherein the one or more surfactants are non-ionic        surfactants.    -   1.72. Any previous Composition, further comprising one or more        surfactants, wherein the one or more surfactants comprise        polysorbate 80, polyoxyl 35 castor oil, or a combination        thereof.    -   1.73. Any foregoing Composition, further comprising one or more        surfactants, wherein the cannabinoid-infused powder is obtained        or obtainable by contacting the edible carrier with an edible        oil comprising the cannabinoid active pharmaceutical ingredient        and a second edible oil, drying and pulverizing the infused        substance thus obtained, and adding one or more surfactants in        dry form.    -   1.74. Any foregoing Composition, other than Compositions        1.68-1.73, wherein the Composition is substantially        surfactant-free, e.g., wherein the pharmaceutical composition        contains less than 1% of surfactants (other than impurities        derived from the edible oil comprising long chain triglycerides,        such as long chain fatty acids or mono or di-glycerides of long        chain fatty acids).    -   1.75. Any foregoing Composition comprising one or more        antioxidants, e.g., one or more non-polar antioxidants, e.g.,        selected from mixed tocopherols, quercetin, curcumin or other        suitable oil-soluble antioxidants, e.g., in an amount effective        to slow or halt the degradation of the non-polar active        ingredient(s).    -   1.76. Any foregoing Composition comprising one or more        anti-microbial agents, e.g. anti-bacterial and/or anti-fungal        agents, for example non-polar, natural anti-bacterial and/or        anti-fungal agents, e.g., selected from among thymol, carvacrol,        lauric acid, or other naturally occurring anti-bacterial and/or        anti-fungal agents, e.g., in an anti-microbially effective        amount, e.g., in an amount effective to kill microbes or slow or        halt microbial growth, e.g. wherein the microbes are bacteria        and/or fungi.    -   1.77. Any foregoing Composition wherein, after oral        administration, at least 40%, e.g., at least 50%, e.g., at least        60%, of the API absorbed is absorbed via the lymphatic system        rather than the portal vein absorption, e.g., as measured in        rats with cannulated intestinal lymph duct and portal veins,        e.g., as described in Example 2.    -   1.78. Any foregoing Composition wherein, after oral        administration, the liver metabolism of the API within one hour        of oral administration is reduced relative to the liver        metabolism of the API within one hour of oral administration of        a formulation that does not comprise long chain triglycerides.    -   1.79. Any foregoing Composition wherein, after oral        administration, the total bioavailability of the API is at least        70%, e.g., at least 80%, e.g., at least 90%.    -   1.80. Any foregoing Composition wherein the bioavailability        after oral administration is substantially the same, e.g., ±10%,        in fed and fasted subjects.    -   1.81. Any foregoing Composition wherein, after oral        administration, the API is present in the cerebrospinal fluid        (CSF) at levels greater than the levels in the plasma.    -   1.82. Any foregoing Composition for use in any of Methods 1, et        seq.

The disclosure further provides a pharmaceutical composition comprisinga cannabinoid-infused powder, wherein the cannabinoid-infused powdercomprises a cannabinoid active pharmaceutical ingredient (API)(e.g. CBD,CBG, CBN, or combinations thereof), an edible oil comprising long chaintriglycerides, and an edible carrier, e.g., a pharmaceutical compositionaccording to any of Composition 1, et seq., for use in any of Methods 1,et seq.

The disclosure further provides the use of a cannabinoid activepharmaceutical ingredient (API)(e.g. CBD, CBG, CBN, or combinationsthereof) in the manufacture of a pharmaceutical composition comprising acannabinoid-infused powder, wherein the cannabinoid-infused powdercomprises a cannabinoid active pharmaceutical ingredient (API)(e.g. CBD,CBG, CBN, or combinations thereof), an edible oil comprising long chaintriglycerides, and an edible carrier, e.g., a pharmaceutical compositionaccording to any of Composition 1, et seq., for a treatment inaccordance with any of Methods 1, et seq.

The foregoing pharmaceutical compositions of Composition 1, et seq. aregenerally prepared by mixing the ingredients, drying the mixture usingdry heat, e.g., in an oven, pulverizing the dried mixture, andformulating into unit dose form, e.g., by filling capsules to providethe desired unit dose amounts. For example, the cannabinoid-infusedpowder may be made by contacting the edible carrier with an edible oilcomprising the cannabinoid active pharmaceutical ingredient and a secondedible oil, and drying and pulverizing the infused substance thusobtained. Optional ingredients such as surfactants, anti-oxidants,and/or anti-microbial agents may be added prior to the drying andpulverizing the infused substance, so as to form part of thecannabinoid-infused powder, or may be added to the cannabinoid-infusedpowder in formulating the pharmaceutical compositions.

Unless stated otherwise, all percentages of composition components givenin this specification are by weight based on a total composition orformulation weight of 100%.

The compositions and formulations as provided herein are described andclaimed with reference to their ingredients, as is usual in the art. Aswould be evident to one skilled in the art, the ingredients may in someinstances react with one another, so that the true composition of thefinal formulation may not correspond exactly to the ingredients listed.Thus, it should be understood that the invention extends to the productof the combination of the listed ingredients.

As used throughout, ranges are used as shorthand for describing each andevery value that is within the range. Any value within the range can beselected as the terminus of the range. In addition, all references citedherein are hereby incorporated by referenced in their entireties. In theevent of a conflict in a definition in the present disclosure and thatof a cited reference, the present disclosure controls.

EXAMPLES Example 1: Exemplary Formulations

Formulations A, B, C and D are prepared in the form of capsules, whereineach capsule contains:

Ingredient (mg Formulation Formulation Formulation Formulation percapsule) A B C D Silicon 63.43 49.99 60.00 55.55 dioxide (mg) (ca. 15%)(ca. 12%) (ca. 14%) (ca. 11.7%) Tapioca 58.83 328.41 303.00 364.90starch (mg) (ca. 14%) (ca. 77%) (ca. 71%) (ca. 76.7%) Hemp distillate31.71 A (mg) (ca. 7.6%) Hemp distillate 25.00 B (mg) (ca. 5.8%) Hempdistillate 30.00 C (mg) (ca. 7%) Hemp distillate 27.77 D (mg) (ca. 5.8%)Sunflower oil 31.71 25.00 30.00 27.77 (mg) (ca. 7.6%) (ca. 5.8%) (ca.7%) (ca. 5.8%) Ginseng (mg) 150.00 (ca. 36%) Ginkgo biloba 80.00 (mg)(ca. 19%) Melatonin (mg) 2.50 (ca. 0.6%) Total 415.68 428.40 425.50476.00 (100%) (100%) (100%) (100%)

The hemp distillate components of the foregoing formulations are colddistillates from Cannabis plant material comprising >90% cannabinoids(primarily CBD, together with lesser amounts of CBG, CBN, and othercannabinoids), and <10% Cannabis impurities, e.g., mixed terpenes,waxes, lipids, and/or proteins. In the above formulations:

-   -   31.71 mg of hemp distillate A provides 25 mg CBD (6% of        formulation A) and 2.1 mg CBG (0.5% of formulation A) per        capsule.    -   25 mg of hemp distillate B component provides 20 mg CBD (4.7% of        formulation B) and 1 mg CBN (0.23% of formulation B) per        capsule.    -   30 mg of hemp distillate C component provides 27 mg CBD (6% of        formulation C) and 1.9 mg CBN (0.45% of formulation C) per        capsule.    -   27.77 mg of hemp distillate D component provides 20.05 mg CBD        (4.2% of formulation D) per capsule.

The formulations are prepared by mixing the ingredients in theproportions described, in an amount sufficient to provide the desirednumber of capsules, drying the mixture in an oven, pulverizing the driedmixture, and filling hard gel capsules with the powder thus obtained, inthe amounts per capsule as described above.

Example 2: Bioavailability of Test Formulations

Differences in absorption from the GI tract of rats given severaldifferent preparations of cannabidiol (CBD) are evaluated. It isbelieved that, with a suitable formulation, the lipophilic CBD can bepreferentially directed (channeled) towards lymphatic absorption versusportal vein absorption, thus avoiding metabolism in the liver andresulting in higher systemic blood levels.

Male adult rats with cannulated intestinal lymph duct and portal veinhave their samples collected after administering equidose quantities ofdifferent preparations. In order to get systemic pharmacokinetics,another set of rats with only jugular vein cannula is studied under thesame conditions. In both groups of animals, a gastric infusion tube isintroduced into the stomach through a fundal incision and the incisionis sealed off by a purse string suture.

For Experiment 1, five days before an experiment is planned, the animalundergoes surgery for the installation of various cannulae. Underisoflurane anesthesia, the portal vein is cannulated. The animal is thenallowed to recover for 3 days prior to the intestinal lymph ductcannulation. A stomach infusion tube is also installed. After overnightrecovery, the lymph catheter collects chylomicrons produced and secretedby the small intestinal epithelial cells (enterocytes). The portal veinallows blood sampling when lymph samples are collected. This allows acomparison of lymphatic versus portal transport of CBD when infused withdifferent vehicles. Rats with satisfactory catheters are used for eachtest article. Each rat receives an equal dose of the test article towhich they have been assigned as a slow gavage five minutes. Lymphsamples are sampled for 1 h before gavage and then hourly for 6 h. Incertain experiments, 30 min. lymph samples are taken to present a betterpicture of the lymphatic transport. Other experiments to go more than 6h to 8 h. At each hour time point of lymph collection 0.2 ml of blood istaken from the portal vein to isolate the plasma for analyses. Thelymphatic flow usually varies between 2-4 ml per hour.

In Experiment 2, animals are fasted overnight prior to surgery. In themorning, under isofluorane anesthesia, the jugular vein is cannulatedand the stomach is intubated as described above. A similar mixture asthose tested in Experiment 1 is administered into the stomach and bloodsamples is collected as portal vein samples described above and theplasma is analyzed for CBD content. Jugular vein blood (0.2 ml) is takenfrom the rats and analyzed for CBD content.

Blood collected from the portal and jugular catheters is quickly spunand plasma is collected, frozen, and stored at −80 C. Intestinal lymphsamples are frozen and stored at −80 C. Some of this lymph isfractionated into chylomicron and other fractions for CBD assay usingLC-MS.

The concentrations of CBD for each animal at each interval is plottedfor each animal and summarized across all animals in a cohort for mean,SD, and SEM. The portal vein vs. thoracic duct concentrations withineach group are compared with a T test. The portal vein, thoracic ductand systemic values among the four groups are compared with ANOVAtesting.

A CBD-infused powder (Formulation D of Example 1) shows significantlyhigher C_(max), faster T_(max), and approximately double AUC over sixhours, indicating faster and greater absorption of the CBD, compared toa commercial CBD tincture comprising a medium chain triglyceride (MCT)oil and hemp extract comprising CBD (MedTerra). These data are set forthin FIG. 1 and in the following table:

Systemic Pharmacokinetics Mean C_(max) Mean T_(max) Mean AUC Testformulation N ng/mL (SD) Minutes ng*hr/mL (SD) Formulation D 515.45(7.46) 72 60.3(18.0) MedTerra 5 8.35(0.83) 276 29.7(7.9)*

1. A method of a. treating a condition responsive to cannabinoidtherapy, e.g., selected from pain, anxiety, nausea, insomnia, anddysphoria, by delivery of a cannabinoid to the lymphatic system; or b.enhancing delivery of a cannabinoid, e.g., CBD, CBG, and/or CBN, to thecentral nervous system; or c. reducing first pass metabolism of acannabinoid, e.g., CBD, CBG, and/or CBN; or d. reducing food effects inadministration of a cannabinoid, e.g., CBD, CBG, and/or CBN; e. reducingthe dose of opiate needed to relieve pain in a patient receiving opioidtreatment; or f. treating, mitigating, or inhibiting a conditionresponsive to CBD, e.g., a viral infection, e.g. a SARS-CoV-2 infection;comprising orally administering to a patient in need thereof, aneffective amount of a pharmaceutical composition comprising acannabinoid-infused powder, wherein the cannabinoid-infused powdercomprises a cannabinoid active pharmaceutical ingredient (API) selectedfrom CBD, CBG, CBN, and combinations thereof; an edible oil comprisinglong chain triglycerides; and an edible carrier.
 2. The method of claim1 wherein the fatty acid content of the edible oil comprising long chaintriglycerides consists of at least 95% C₁₆ and/or C₁₈ fatty acids. 3.The method of claim 2 wherein the cannabinoid API comprises (i) CBD andCBG in a weight ratio of 5-20:1 of CBD:CBG; e.g., about 10:1 CBD:CBG orabout 25:2 CBD:CBG; (ii) CBD and CBN in a weight ratio of 5-20:1 ofCBD:CBN; e.g., about 10:1 CBD:CBN or about 27:2 CBD:CBN; or (iii) CBD,CBG and CBN in a weight ratio of 1-10:1-10:1-10 (CBD:CBG:CBN).
 4. Themethod of claim 3 wherein the API comprises (a) 4%-6% CBD and (b) 0.2%to 0.7% CBG and/or 0.2% to 0.7% CBN, by weight of thecannabinoid-infused powder; the edible oil comprises 5-10% sunflowerseed oil, by weight of the cannabinoid-infused powder; and the ediblecarrier is selected from silicon dioxide, starch, e.g tapioca starch,dried plant material (e.g., ginseng powder and gingko balboa powder),and mixtures thereof, and comprises 80%-90% by weight of the cannabinoidinfused powder.
 5. A pharmaceutical composition comprisingcannabinoid-infused powders comprising cannabinoid active pharmaceuticalingredient (API) selected from CBD, CBG, CBN, and combinations thereof;an edible carrier; and an edible oil comprising long chaintriglycerides, wherein the fatty acid content of the edible oilcomprising long chain triglycerides consists of at least 95% C₁₆ and/orC₁₈ fatty acids.
 6. The pharmaceutical composition of claim 5 whereinthe cannabinoid API comprises (i) CBD and CBG in a weight ratio of5-20:1 of CBD:CBG; e.g., about 10:1 CBD:CBG or about 25:2 CBD:CBG; (ii)CBD and CBN in a weight ratio of 5-20:1 of CBD:CBN; e.g., about 10:1CBD:CBN or about 27:2 CBD:CBN; or (iii) CBD, CBG and CBN in a weightratio of 1-10:1-10:1-10 (CBD:CBG:CBN).
 7. The pharmaceutical compositionof claim 6 wherein the API comprises (a) 4%-6% CBD and (b) 0.2% to 0.7%CBG and/or 0.2% to 0.7% CBN, by weight of the cannabinoid-infusedpowder; the edible oil comprises 5-10% sunflower seed oil, by weight ofthe cannabinoid-infused powder; and the edible carrier is selected fromsilicon dioxide, starch, e.g tapioca starch, dried plant material (e.g.,ginseng powder and gingko balboa powder), and mixtures thereof, andcomprises 80%-90% by weight of the cannabinoid infused powder.
 8. Thepharmaceutical composition of claim 5, wherein the pharmaceuticalcomposition contains less than 1% of surfactants, other than impuritiesderived from the edible oil comprising long chain triglycerides.